Anti-apoptotic signals of granulocyte-macrophage colony-stimulating factor are transduced via Jak2 tyrosine kinase in eosinophils.
Cytokine-mediated inhibition of eosinophil apoptosis is a mechanism causing tissue eosinophilia. Previously published work suggested that activation of the Lyn-Ras-Raf-1-MAP kinase pathway is obligatory for prevention of eosinophil apoptosis by eosinophil hematopoietins. We demonstrate herein that activation of freshly isolated human blood eosinophils by granulocyte-macrophage colony-stimulating factor (GM-CSF) is associated with increased tyrosine phosphorylation of Jak2. The tyrosine kinase blocker, tyrphostin B42, prevented activation of Jak2 but not Lyn, suggesting that Jak2 is the specific target for tyrphostin B42 in eosinophils. In addition, since Lyn remained unaffected by tyrphostin B42, it is unlikely that Jak2 is required for Lyn activation in this model. To test whether tyrosine phosphorylation of Jak2 is linked to GM-CSF-mediated prolonged eosinophil survival, we determined the effect of tyrphostin B42 on eosinophil viability and apoptosis. Prevention of Jak2 activation by tyrphostin B42 was associated with the inability of GM-CSF to prevent eosinophil apoptosis. These data suggest that disruption of not only the Lyn-Ras-Raf-1-MAP kinase but also the Jak-STAT pathway blocks the ability of eosinophil survival factors to prevent apoptosis in eosinophils.
Simon
H U
HU
Swiss Institute of Allergy and Asthma Research, University of Zurich, Davos, Switzerland. hus@siaf.unizh.ch
Yousefi
S
S
Dibbert
B
B
Levi-Schaffer
F
F
Blaser
K
K
D017209:Apoptosis / Q000276:immunology*; D004804:Eosinophils / Q000276:immunology* / Q000473:pathology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology*; D006801:Humans; D053614:Janus Kinase 2; D011505:Protein-Tyrosine Kinases / Q000276:immunology*; D011518:Proto-Oncogene Proteins; D015398:Signal Transduction / Q000276:immunology*
D011518:Proto-Oncogene Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2